Two recent approaches have provided insights into the possible mechanisms of antigen recognition by different subsets of T lymphocytes, as well as into the structures involved in the first step of a series of events leading towards the induction of T cell activation.
Reports that monoclonal antibodies could interfere with the activation and function of T cells have directed interest to a complex system of molecules on the surface of this subpopulation of lymphocytes. Clonotypic antibodies capable of both inducing and inhibiting functions of human and murine cytotoxic T lymphocytes (CTL), Meuer et al., J. Exp. Med., 157, 705 (1983), Reinherz et al., Proc. Natl. Acad. Sci. (USA), 80, 4104 (1983), Meuer et al., J. Exp. Med., 158, 388 (1983), Staerz et al., Proc. Natl. Acad. Sci. (USA), 81, 1799 (1984), and Lancki et al., J. Exp. Med., 157, 821 (1983), and T helper lymphocytes, Haskins et al., J. Exp. Med., 157, 1149 (1983), Kappler et al., Cell, 34, 727 (1983), Samelson et al., Proc. Natl. Acad. Sci. (USA), 80, 6972 (1983), and Kaye et al., J. Exp. Med., 158, 836 (1983), provided information that indicated that a disulfide-linked heterodimer, first reported by Allison et al., J. Immunol., 129, 2293 (1982), was the most likely candidate for the so-called T cell antigen receptor. In reports to date, clone-specific monoclonal antibodies precipitated a surface protein of 80,000-90,000 daltons that separated into two chains of about 42,000 daltons each upon reduction.
In a second reported approach, the search for T cell-specific cDNA provided additional genetic and structural information for at least one chain of the clonotypic heterodimer, indicating its close resemblance to the proteins of the major histocompatibility complex and to the immunoglobulin chains, Hedrick et al., Nature, 308, 149 (1984), Yanagi et al., Nature, 308, 145 (1984), and Saito et al., Nature, 309, 757 (1984). In particular, the gene for the so-called beta chain was organized in a similar manner as were immunoglobulin genes including a set of variable genes, D segments, joining segments and genes for the constant region of the T cell antigen receptor, Hedrick et al., Nature, 308, 153 (1984), Malissen et al., Cell, 37, 1101 (1984), Chien et al., Nature, 309, 322 (1984), Gascoigne et al., Nature, 310, 387 (1984), and Kavaler et al., Nature, 310, 421 (1984).
The use of clone-specific (i.e., anti-idiotypic) monoclonal antibodies to perform a crude purification of the T cell receptor for the production of "second generation" antibodies that react with subsets of T cells has also been reported. Both a rabbit antiserum against the murine T cell antigen receptor of the T helper subset, McIntyre et al., Cell, 34, 739 (1983), and a rat monoclonal antibody KJ16-133 against a subset of T lymphocytes, Haskins et al., J. Exp. Med., 160, 452 (1984), have been described. KJ16-133 reportedly bound to an allotypic structure on about 20 percent of peripheral T cells in BALB mice and most other strains of laboratory mice. This determinant was absent in a few strains. The KJ16-133 antibody was reported to react with receptors on mature and immature thymocytes, and on both L3T4.sup.+ and Lyt2.sup.+ peripheral T cells, Roehm et al., Cell, 38, 577 (1984).
Hybrid antibodies consisting of two different antibody fragments having two different specificities have been reported. Milstein et al., Immunol. Today, 5, 299 (1984), Nisonoff et al., Arch. Biochem. Biophys., 93, 460 (1961), Milstein et al., Nature, 305, 537 (1983), Kohler et al., Nature, 256, 495 (1975), Hammerling et al., J. Exp. Med., 128, 1461 (1968), Paulus, U.S. Pat. No. 4,444,878, and Ehrlich et al., U.S. Pat. No. 4,355,023. Target-specific effector cells using hetero-cross-linked aggregates containing anti-target cell and anti-F.sub.c portion of IgG receptor antibodies were reported in Karpovsky et al., J. Exp. Med., 160, 1686 (1984).
However, heretofore, no hybrid antibodies have been reported having the T cell antigen receptor specificity in at least one of the antibody combining sites of the hybrid antibody, nor having the capability of inducing cytotoxic effector T lymphocytes that lyse the target cell. Such hybrid antibodies have also not been suggested.